Motor recovery after stroke is accompanied by functional and structural plasticity in cerebral cortex. In this Cooperative Program in Translational Research (U54), a new therapeutic approach, intended to enhance motor recovery via modulation of neuroplasticity, will be tested in rat (Projects 1 and 2) and nonhuman primate (Project 3) models of recovery after cortical ischemic infarct. This new approach, Cortical Stimulation (CS), utilizes low-level electrical stimulation over peri-infarct cortex applied during rehabilitative training procedures. In this unique collaboration of basic and clinical researchers in academia and industry, preclinical models will be used to optimize treatment protocols for upcoming clinical trials funded by industry. In Project 1, the electrical stimulation protocol (frequency, amplitude, temporal pattern, electrode configuration and duration) will be optimized and seizure susceptibility will be examined. Efficacy will be assessed with regard to evoked movement thresholds and motor performance. In Project 2, the rehabilitative training protocol will be optimized by combining CS with different rehabilitative training procedures (constraint-induced movement therapy, reach training, acrobatic training). The efficacy of training procedures will be assessed by motor performance during treatment and follow-up. In Project 3, optimal parameters determined in rat models will be tested for generalizability to a nonhuman primate model of cortical ischemia and recovery. Also, treatment parameters that are less feasible in the rodent model will be assessed in primates. An Oversight/Leadership Core will organize meetings, promote scientific exchange, assist in management of U54 cores and projects and provide data management and biostatistical support. The three projects will be performed at four sites, chosen because the investigators have extensive experience in the field of stroke recovery, and because they form an integrated team that has advanced the initial preclinical studies. Preclinical results will be translated into the clinical program by regular meetings of the preclinical group with the medical director for clinical trials and U54 Steering Committee to discuss a) preclinical findings and their impact on the clinical program, and b) findings from the clinical program that may impact the preclinical studies. It is expected that this program will serve as a model for the introduction of new therapeutic approaches to brain repair that are based on underlying neuroscientific principles.